Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development

Immunity. 2023 Jan 10;56(1):58-77.e11. doi: 10.1016/j.immuni.2022.11.013. Epub 2022 Dec 14.


Obesity-induced chronic liver inflammation is a hallmark of nonalcoholic steatohepatitis (NASH)-an aggressive form of nonalcoholic fatty liver disease. However, it remains unclear how such a low-grade, yet persistent, inflammation is sustained in the liver. Here, we show that the macrophage phagocytic receptor TREM2, induced by hepatocyte-derived sphingosine-1-phosphate, was required for efferocytosis of lipid-laden apoptotic hepatocytes and thereby maintained liver immune homeostasis. However, prolonged hypernutrition led to the production of proinflammatory cytokines TNF and IL-1β in the liver to induce TREM2 shedding through ADAM17-dependent proteolytic cleavage. Loss of TREM2 resulted in aberrant accumulation of dying hepatocytes, thereby further augmenting proinflammatory cytokine production. This ultimately precipitated a vicious cycle that licensed chronic inflammation to drive simple steatosis transition to NASH. Therefore, impaired macrophage efferocytosis is a previously unrecognized key pathogenic event that enables chronic liver inflammation in obesity. Blocking TREM2 cleavage to restore efferocytosis may represent an effective strategy to treat NASH.

Keywords: TREM2; chronic inflammation; efferocytosis; nonalcoholic steatohepatitis; proinflammatory cytokines.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Humans
  • Inflammation / pathology
  • Liver / pathology
  • Membrane Glycoproteins
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Obesity / pathology
  • Overnutrition* / pathology
  • Receptors, Immunologic


  • TREM2 protein, human
  • Membrane Glycoproteins
  • Receptors, Immunologic